A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy
Abstract
:1. Introduction
2. Methodology
2.1. Vocabulary, Academic Databases, and Searching Strategy
2.2. Inclusion and Exclusion Criteria
2.3. Number of Entries
2.4. Number of Results
3. Results and Discussions
3.1. FMT
3.2. Synbiotics
3.3. Probiotics
4. Current Status of RCTs
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Registered Number | Total Number of Patients | Randomization/ Allocation | Intervention | Donor | Follow-Up | Reference |
---|---|---|---|---|---|---|
FMT | ||||||
NCT02636647 | n = 80 patients n = 20 per study | 1:1 | frozen-then-thawed FMT | A single donor enriched in Lachnospiraceae and Ruminococcaceae | 5 months | [32] |
NS | >12–15 months | [33] | ||||
NCT03152188 | capsular FMT | 5 months | [34] | |||
5 months | [35] | |||||
SYNBIOTICS | ||||||
No | n = 55 patients | n = 20 Synbiotics n = 20 Fermentable fiber n = 15 Placebo | 30 days of Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei subspecies paracasei, and Lactobacillus plantarum of 1010 CFU + 10 g of fermentable fiber (2.5 g per beta glucan, inulin, pectin, and resistant starch) each | NS | [36] | |
ACTRN12610001021066 | n = 61 initially included, but remained n = 49 patients | n = 12 Synbiotics n = 12 BCAAs n = 13 Synbiotics + BCAAs n = 12 Placebo | Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei subspecies paracasei, and Lactobacillus plantarum of 1011 CFU + 10 g of fermentable fiber (2.5 g oat bran, pectin, inulin, and resistant starch) each 10 g crystalline starch for placebo | At 1–2 months | [37] | |
PROBIOTICS | ||||||
No | n = 66 initially included, but remained n = 60 patients | n = 30 Bifidobacterium longum + FOS n = 30 Placebo | 30–60–90 days of Bifidobacterium longum W11 + FOS (2.5 g), and vitamin B1 (1.4 mg), vitamin B2 (1.6 mg), vitamin B6 (2.0 mg), vitamin B12, (1.0 mg) | After 30 days | [38] | |
No | n = 240 patients | n = 50 Controls n = 190 Cirrhotics initially included, but remained n = 105 | 1 month of 30–60 mL lactulose/day; 1 capsule 3 times/day Streptococcus faecalis 6 × 107, Clostridium butyricum 4 × 106, Bacillus mesentricus 2 × 106, lactic acid bacillus 1 × 108 30–60 mL lactulose + Streptococcus faecalis 6 × 107, Clostridium butyricum 4 × 106, Bacillus mesentricus 2 × 106, lactic acid bacillus 1 × 108; | 1 month | [39] | |
No | n = 66 initially included, but remained n = 25 | n = 8 No treatment n = 17 Yogurt | 60 days of Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei Bifidobacteria | Initial, and after 30–60 days | [40] | |
No | n = 125 patients | n = 62 patients Lactulose n = 63 Bifidobacterium + FOS | 30–60 days of Bifidobacterium + FOS lactulose | After 30–60 days | [41] | |
No | n = 43 patients | n = 21 Probiotics n = 22 Placebo | 3 times/day for 4 weeks of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Sacharomyces boulardi 1.25 × 109 | NS | [42] | |
No | n = 422 initially included, but remained n = 322 | n = 162 No MHE n = 160 MHE (n = 40 No treatment, n = 40 Lactulose, n = 40 Probiotics, n = 40 LOLA) | 3 months of standard treatment divided in dose for stool frequency (2–3 semisolid stools) 30–60 mL lactulose probiotics 1.1 × 1011 CFU 6 g LOLA 3 times/day | After 3 months | [43] | |
No | n = 360 initially included, but remained n = 235 | n = 77 Probiotics n = 78 No therapy n = 80 Lactulose | 30–60 mL lactulose (2/3 doses to pass 2–3 semisoft stools) three capsules/day 1.125 × 10 of Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, Streptococcus salivarius subsp. thermophiles no therapy | After 3 months/12 months | [44] | |
No | n = 150 initially included, but remained n = 30 | ITT n = 18 LGG n = 19 Placebo Per protocol n = 14 LGG n = 16 Placebo | Lactobacillus GG > 5 × 1010 CFU/g (5.1 × 1010, 5.3 × 1010, 6.1 × 1010) | Initial, and at 4–8 weeks | [45] | |
CTRI/2012/07/002807 | n = 160 patients | n = 74 Control n = 86 Probiotics | 1 capsule 3 times/day of Bifidobacterium breve, Bifidobacteriumlongum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, Streptococcus thermophilus 1.1 × 1011 CFU | After 3–6 months | [46] | |
No | n = 317 initially included, but remained n = 124 | n = 30 Placebo n = 31 LOLA n = 31 Rifaximin n = 32 Probiotics | 2 months of 18 g LOLA 2 sachets 3 times/day 400 mg rifaximin 3 times/day 5.0 × 109 CFU of Lactobacillus acidophilus (0.7 × 109), Lactobacillus rhamnosus (0.6 × 109), Lactobacillus plantarum (0.6 × 109), Lactobacillus casei (0.6 × 109), Bifidobacterium longum (0.6 × 109), Bifidobacterium infantis (0.6 × 109), Bifidobacterium breve (0.6 × 109), Streptococcus thermophilus (0.6 × 109), Sacchromyces boulardi (0.1 × 109) | For 2 months | [47] | |
No | n = 221 initially included, but remained n = 130 | n = 64 Placebo n = 66 Probiotics | 1 month of Lactobacillus paracasei DSM 24733, Lactobacillus plantarum DSM 24730, Lactobacillus acidophilus DSM 24735, Lactobacillus delbrueckii subspecies bulgaricus DSM 24734, Bifidobacterium longum DSM 24736, Bifidobacterium infantis DSM 24737, Bifidobacterium breve DSM 24732, Streptococcus thermophilus DSM 24731 of 9 × 1011 CFU 24 weeks ofcorn flour placebo | For 6 months | [48] | |
NCT01008293 | n = 562 initially included, but remained n = 227 | n = 107 Without MHE n = 120 MHE (n = 60 Lactulose n = 60 Probiotics) | 2 months of 30–60 mL/day (2/3 soft stools) 2 capsules/day of 4.5 × 1011 CFU of Lactobacillus acidophilus DSM 24735, Lactobacillus plantarum DSM 24730, Lactobacillus paracasei DSM 24733, Lactobacillus delbrueckii subsp. bulgaricus DSM 24734, Bifidobacterium longum DSM 24736, Bifidobacterium breve DSM 24732, Bifidobacterium infantis DSM 24737, Streptococcus thermophilus DSM 24731 of 1.125 × 1011 | For 2 months | [49] | |
No | n = 67 patients | n = 30 Probiotics n = 37 Control | 3 months of 1500 mg 3 times/day of Clostridium butyricum (CGMCC0313-1) of >1.0 × 107 CFU/g, Bifidobacterium infantis (CGMCC0313-2) of 1.0 × 106 CFU/g | NS | [50] | |
NCT01686698 | n = 121 initially included, but remained n = 36 | n = 18 Placebo n = 18 Probiotics | 4.4 g sachet containing 4.5 × 1011 2 times/day (every 12 h) for 12 weeks of Lactobacillus paracasei DSM 24733, Lactobacillus acidophilus DSM 24735, Lactobacillus delbrueckii subsp. bulgaricus DSM 24734, Lactobacillus plantarum DSM 24730, Bifidobacterium breve DSM 24732, Bifidobacterium longum DSM 24736, Bifidobacterium infantis DSM 24737, Streptococcus thermophilus DSM 24731 | At baseline, week 6, week 12 (end of treatment), and week 20 (end of study) | [51] | |
No | n = 110 initially included, but remained n = 92 | n = 43 Placebo n = 44 Lactobacillus casei Shirota | 6 months of 65 mL (6.5 × 109 CFU) containing Lactobacillus casei Shirota 3 times/day | At baseline, day 0, day 14, 1–3–6 months | [52] | |
NCT05231772 | n = 198 initially included, but remained n = 40 | n = 16 Placebo n = 24 Probiotics | 3 months of 250 mg 2 times/day of Saccharomyces boulardii | 3 months | [53] |
Precipitating Factors | Proportion or Number of Patients or Episodes | Reference | ||
---|---|---|---|---|
Pneumonia Variceal bleed Hyponatremia Constipation | 1 1 1 1 | [32] | ||
Acute kidney injury (2) **, pneumonia (1) **, anasarca (1) **, lactulose non-adherence, renal insufficiency (without HE) Infections HE Electrolyte abnormalities | 1 2 2 1 | [34] | ||
Variceal bleed UTI with sepsis SBP Pneumonia with sepsis Constipation Unknown | 4 vs. 4 vs. 5 0 vs. 1 vs. 2 4 vs. 3 vs. 7 2 vs. 0 vs. 3 3 vs. 5 vs. 8 5 vs. 9 vs. 12 | [44] | ||
Variceal bleed SBP Constipation UTI Pneumonia | 2 vs. 3 1 vs. 4 3 vs. 3 1 vs. 2 0 vs. 2 | [46] | ||
Variceal bleed Constipation Infections Overall SBP Pneumonia Other infections * Diuretics/renal dysfunction Spontaneous (%) | 16 (24.2) vs. 17 (26.6) 37 (56.1) vs. 33 (51.6) - 18 (27.3) vs. 20 (31.3) 14 (21.2) vs. 8 (12.5) 2 (3.0) vs. 6 (9.4) 2 (3.0) vs. 6 (9.4) 4 (6.1) vs. 6 (9.4) 2 (3.0) vs. 1 (1.6) | [48] | ||
Variceal bleed Sepsis Alcoholic hepatitis Superimposed acute vital hepatitis Spontaneous | 4 10 2 2 4 | [49] | ||
SPB Lower respiratory tract infection UTI Gastroenteritis Occult sepsis Other Ascites Variceal bleed Jaundice HE Hepatorenal syndrome | Day 0 0 vs. 0 2.33 vs. 0 0 vs. 2.27 2.33 vs. 0 0 vs. 0 6.98 vs. 0 2.33 vs. 6.82 0 vs. 0 2.33 vs. 4.55 0 vs. 2.27 0 vs. 2.27 | Month 1 0 vs. 0 2.44 vs. 0 0 vs. 0 0 vs. 0 0 vs. 0 2.44 vs. 0 4.86 vs. 5.13 0 vs. 1.27 0 vs. 2.56 0 vs. 0 0 vs. 0 | Month 6 0 vs. 0 0 vs. 0 0 vs. 0 0 vs. 0 0 vs. 0 5.72 vs. 3.23 5.71 vs. 6.45 0 vs. 1.52 0 vs. 0 0 vs. 0 0 vs. 0 | [52] |
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Ilie, O.-D.; Duta, R.; Nita, I.-B.; Dobrin, I.; Gurzu, I.-L.; Girleanu, I.; Huiban, L.; Muzica, C.; Ciobica, A.; Popescu, R.; et al. A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy. Medicina 2023, 59, 2143. https://doi.org/10.3390/medicina59122143
Ilie O-D, Duta R, Nita I-B, Dobrin I, Gurzu I-L, Girleanu I, Huiban L, Muzica C, Ciobica A, Popescu R, et al. A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy. Medicina. 2023; 59(12):2143. https://doi.org/10.3390/medicina59122143
Chicago/Turabian StyleIlie, Ovidiu-Dumitru, Raluca Duta, Ilinca-Bianca Nita, Irina Dobrin, Irina-Luciana Gurzu, Irina Girleanu, Laura Huiban, Cristina Muzica, Alin Ciobica, Roxana Popescu, and et al. 2023. "A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy" Medicina 59, no. 12: 2143. https://doi.org/10.3390/medicina59122143